A wide variety of environmental chemicals (organochlorine and organophosphate insecticides, insecticide synergists, various herbicides, chemical carcinogens) have been shown experimentally to alter the activity of hepatic drug metabolizing enzymes and thus influence the toxicity of other pesticides and many other foreign chemicals, including drugs. We propose to continue the investigation of toxicological interactions between pesticides and foreign chemicals, and to emphasize the study of interactions in which a known carcinogen participates as one of the interactants. Specifically we will explore toxicological interactions between drugs, carcinogens and other foreign compounds in relation to the following types of pesticides: (a) inducers of hepatic microsomal enzymes (organochlorine insecticides, herbicides), and (b) inhibitors of microsomal enzymes (organophosphate insecticides and methylenedioxyphenyl pesticide synergists). These interaction studies will involve observations of mortality in mice and rats treated with combinations of selected agents in different sequence and time intervals, measurement of activity of enzymes affecting metabolism of the chemicals under study, and measurement of levels of the chemicals and their metabolites in blood and other tissues, in the attempt to define mechanisms involved in observed toxicity interactions. It is hoped that the results of these studies will add to knowledge about the nature and mechanisms of toxicologic interactions that may occur between chemicals in our environment, and aid in the assessment of their hazards to public health and in developing methods to prevent their potentially harmful effects.